1.Synthesis and antimelanoma activity of reversed amide analogues of N-acetyl-4-S-cysteaminylphenol.
Nicoll K1, Robertson J, Lant N, Kelland LR, Rogers PM, Robins DJ. Oncol Res. 2006;16(2):97-106.
The melanin biosynthetic pathway from tyrosine is a potential target for combating malignant melanoma. N-Acetyl-4-S-cysteaminylphenol 1 is a previously synthesized analogue of tyrosine that probably acts by this pathway. It interferes with cell growth and proliferation via selective oxidation in melanocytes to an oquinone that can alkylate cellular nucleophiles. We previously synthesized a range of analogues of the original lead compound 1 most of which displayed greater cytotoxicity than 1. Eighteen new analogues with the amide group reversed have now been synthesized and tested for antimelanoma activity. Most of these reverse amides showed greater cytotoxicity than N-acetyl-4-S-cysteaminylphenol towards five representative melanoma cell lines. The highest cytotoxicity was observed for the piperidine and hexamethyleneimine derivatives 7, 8, 12, 13, and 17 and the catechol 18. The most active compound, 7, had cytotoxicity comparable to cisplatin against the five melanoma cell lines.
2.Synthesis and antimelanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol.
Lant NJ1, McKeown P, Kelland LR, Rogers PM, Robins DJ. Anticancer Drug Des. 2000 Aug;15(4):295-302.
N-Acetyl-4-S-cysteaminylphenol (1) has been shown by Jimbow and co-workers to possess useful antimelanoma activity. It is an analogue of a biosynthetic intermediate in the pathway to melanin and probably acts as a prodrug, being oxidized to an o-quinone which reacts with essential enzymes containing sulphydryl groups resulting in interference with cell growth and proliferation. We have synthesized a range of analogues of 1 by varying the acyl portion of the amide with the intention of increasing the lipophilicity of the compounds. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. The most active of these compounds, N-[2-[(4-hydroxyphenyl)thiol]ethyl]cyclohexanecarboxamide (9), showed promising selectivity (lack of cytotoxicity) on the non-melanotic cell line SK-Mel-24 and on an ovarian cell line. A significant improvement in antimelanoma activity was observed with a new type of analogue containing three carbon atoms between the sulphur and nitrogen.
3.Synthesis and antimelanoma activity of tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol.
Pearson VC1, Ferguson J, Rogers PM, Kelland LR, Robins DJ. Oncol Res. 2003;13(11):503-12.
The biosynthetic pathway to melanin is a realistic target for therapeutic intervention in the development of new drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of a biosynthetic intermediate in the pathway to melanin. It probably acts as a prodrug and is oxidized selectively in melanocytes to an o-quinone, which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We have now prepared 12 new compounds with varying acyl portions and three different substituents on the nitrogen of the amide in order to increase lipophilicity and to reduce the possibility of hydrolysis of the amides. Most of the tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide.
4.Sulfur containing tyrosine analogs can cause selective melanocytotoxicity involving tyrosinase-mediated apoptosis.
Minamitsuji Y1, Toyofuku K, Sugiyama S, Yamada K, Jimbow K. J Investig Dermatol Symp Proc. 1999 Sep;4(2):130-6.
Sulfur-containing tyrosine analogs such as 4-S-cysteaminylphenol (4-S-CAP) and its N-acetyl derivative, N-acetyl-4-S-CAP, are tyrosinase substrates and can cause selective cytotoxicity or cell death of melanocytes and melanoma cells. It is not clear, however, if the cytotoxicity derives from a cytostatic or cytocidal effect. The latter can also be either apoptotic or necrotic. This paper summarizes our attempt to clarify the nature of melanocytotoxicity and cell death by using a new derivative of 4-S-CAP, N-propionyl-4-S-CAP (NPr-CAP). The i.p. administration of NPr-CAP caused marked depigmentation of black hair follicles in C57 mice. At 12 h postadministration of NPr-CAP, follicular melanocytes showed histochemical and morphologic features indicative of apoptosis by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and electron microscopy. The agarose gel electrophoresis of DNA from drug-treated melan a2 cells, an immortal melanocyte line of C57 black mice, showed the nucleosomal DNA ladder pattern.